Efficient synthetic routes for the preparation of rhinovirus protease inhibitors and key intermediates

ABSTRACT

Efficient synthetic routes for the preparation of rhinovirus protease inhibitors of formula I, as well as key intermediates useful in those synthetic routes. These compounds of formula I, as well as pharmaceutical compositions that contain these compounds, are suitable for treating patients or hosts infected with one or more picornaviruses.

RELATED APPLICATION DATA

[0001] This application relates to U.S. Provisional Patent ApplicationSerial No. 60/150,358, filed on Aug. 24, 1999 and is acontinuation-in-part of U.S. application Ser. No. 09/643,864, filed Aug.23, 2000. The above-mentioned applications are relied upon andincorporated herein by reference.

[0002] This application also relates to U.S. Provisional PatentApplication Serial No. 60/150,365 (Attorney Docket No. 0125.0027), alsofiled Aug. 24, 1999, entitled “Efficient Methods For The Preparation OfRhinovirus Protease Inhibitors, Key Intermediates And A ContinuousMembrane Reactor Useful For The Preparation Of The Same” having named asinventors: J. Tao, S. Babu, R. Dagnino, Jr., Q. Tian, T. Remarchuk, K.McGee, N. Nayyar, and T. Moran. The aforementioned application alsorelates to synthetic routes for the preparation of rhinovirus proteaseinhibitors, as well as key intermediates useful in their preparation.

TECHNICAL FIELD AND INDUSTRIAL APPLICABILITY OF INVENTION

[0003] The present invention relates to an improved process for thepreparation ofethyl-3-{(5′-methylisoxazole-3′-carbonyl)-L-ValΨ(COCH₂)-L-(4-F-Phe)-L-((S)-Pyrrol-Ala)}-E-propanoate,its analogs and of pharmaceutically acceptable salts thereof. Thepresent invention also includes a novel group of key intermediatecompounds to be used in the above process.

BACKGROUND OF THE INVENTION

[0004] Picornaviruses are a family of tiny non-envelopedpositive-stranded RNA-containing viruses that infect humans and otheranimals. These viruses include the human rhinoviruses, humanpolioviruses, human coxsackieviruses, human echoviruses, human andbovine enteroviruses, encephalomyocarditis viruses, meningitis viruses,foot and mouth viruses, hepatitis A virus, and others. The humanrhinoviruses are a major cause of the common cold.

[0005] Proteolytic 3C enzymes are required for the natural maturation ofthe picornaviruses. Thus, inhibiting the activity of these proteolytic3C enzymes should represent an important and useful approach for thetreatment and cure of viral infections of this nature, including thecommon cold.

[0006] Some small-molecule inhibitors of the enzymatic activity ofpicornaviral 3C protease (i.e., antipicornaviral compounds) have beenrecently discovered. See, for example: U.S. patent application Ser. No.08/850,398, filed May 2, 1997, by Webber et a.; U.S. patent applicationSer. No. 08/991,282, filed Dec. 16, 1997, by Dragovich et al.; and U.S.patent application Ser. No. 08/991,739, filed Dec. 16, 1997, by Webberet al. These U.S. patent applications, the disclosures of which areincorporated herein by reference, describe certain antipicornaviralcompounds and methods for their synthesis.

[0007] More recently, an especially potent group of antipicornaviralagents have been discovered as set forth in U.S. patent application Ser.No. 60/098,354, (the '354 application) filed Aug. 28, 1998, by Dragovichet al., which is herein incorporated by reference. This applicationdiscloses, inter alias, a group of antipicornaviral agents of generalformula I. A particularly promising compound,ethyl-3-{(5′-methylisoxazole-3′-carbonyl)-L-ValΨ(COCH₂)-L-(4-F-Phe)-L-((S)-Pyrrol-Ala)}-E-propanoate,falling within the scope of this group, exhibits excellent antiviralproperties against a plethora of Rhinoviral serotypes and is currentlyin human clinical antipicornavirus agents and suitable synthetic methodsfor their synthesis. See Structure-Based Design, Synthesis, andBiological Evaluation of Irreversable Human Rhinovirus 3C ProteasesInhibitors. 3. For example, General Method V therein discloses a generalmethod for synthesizing the compounds of formula I involving subjectinga carboxylic acid of general formula BB to an amide-forming reactionwith an amine of general formula P to provide a final product CC, asshown below.

[0008] The '354 application further discloses methods for synthesizingthe intermediates of general formulae BB and P, and teaches methods forcarrying out the amide-forming reaction referred to above. Thus, the'354 application teaches suitable methods for synthesizing the compoundsof general formula I from a carboxylic acid BB (within the scope of thecompounds of general formula II referred to below) and the compounds ofgeneral formula P (the same as the compounds of general formula IIIreferred to below.) Similarly, two recent publications by Dragovich etal. disclose antipicornavirus agents and suitable synthetic methods fortheir synthesis. See Structure Activity Studies ofKetomethylene-Containing Peptidomimetics, Dragovich et al., Journal ofMedicinal Chemistry, ASAP, 1999; and Structure-Based Design, Synthesis,and Biological Evaluation of Irreversable Human Rhinovirus 3C ProteasesInhibitors. 4. Incorporation of P ₁ Lactam Moieties as L-GlutamineReplacements, Dragovich et al., Journal of Medicinal Chemistry, ASAP,1999. These aforementioned articles are herein incorporated by referencein their entirety.

[0009] However, there is still a desire to discover improved, moreefficient, processes and novel intermediates for use in the syntheses ofthe compounds of the group of antipicornaviral agents. In particular,there is a need for improved methods for synthesizing the compounds ofgeneral formulae II and III.

SUMMARY OF THE INVENTION

[0010] The present invention relates to the discovery of a costeffective and efficient process for the preparation of theantipicornaviral agents of formula I, such as compoundethyl-3-{(5′-methylisoxazole-3′-carbonyl)-L-ValΨ(COCH₂)-L-(4-F-Phe)-L-((S)-Pyrrol-Ala)}-E-propanoate,as well as intermediates which are useful in that synthesis.

[0011] The antipicornaviral agents of formula I comprise:

[0012] wherein R₁ is H, F, an alkyl group, OH, SH, or an O-alkyl group;

[0013] R₂ and R₃ are each independently H;

[0014]  where n is an integer from 0 to 5, A₁ is CH or N, A₂ and each A₃are independently selected from C(R₄₁)(R₄₁), N(R₄₁), S, S(O), S(O)₂, andO, and A₄ is NH or N₄₁, where each R₄₁ is independently H or loweralkyl, provided that no more than two heteroatoms occur consecutively inthe above-depicted ring formed by A₁, A₂, (A₃)_(n), A₄ and C═O, and atleast one of R₂ and R₃ is

[0015] R₅ and R₆ are each independently H, F, an alkyl group, acycloalkyl group, a heterocycloalkyl group, an aryl group, or aheteroaryl group;

[0016] R₇ and R₈ are each independently H, an alkyl group, a cycloalkylgroup, a heterocycloalkyl group, an aryl group, a heteroaryl group,—OR₁₇, —SR₁₇, —NR₁₇R₁₈, —NR₁₉NR₁₇R₁₈, or —NR₁₇OR₁₈, where R₁₇, R₁₈, andR₁₉ are each independently H, an alkyl group, a cycloalkyl group, aheterocycloalkyl group, an aryl group, a heteroaryl group, or an acylgroup, provided that at least one of R₇ and R₈ is an alkyl group, anaryl group, a heteroaryl group, —OR₁₇, —SR₁₇, —NR₁₇R₁₈, —NR₁₉NR₁₇R₁₈, or—NR₁₇OR₁₈;

[0017] R₉ is a five-membered heterocycle having from one to threeheteroatoms selected from O, N, and S; and

[0018] Z and Z₁ are each independently H, F, an alkyl group, acycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroarylgroup, —C(O)R₂₁, —CO₂R₂₁, CN, —C(O)NR₂₁R₂₂, —C(O)NR₂₁OR₂₂, —C(S)R₂₁,—C(S)NR₂₁ R₂₂, —NO₂, —SOR₂₁, —SO₂R₂₁, —SO₂NR₂₁R₂₂, —SO(NR₂₁)(OR₂₂),—SONR₂₁, —SO₃R₂₁, —PO(OR₂₁)₂, —PO(R₂₁)(R₂₂), —PO(NR₂₁R₂₂)(OR₂₃),—PO(NR₂₁R₂₂)(NR₂₃R₂₄), —C(O)NR₂₁NR₂₂R₂₃, or —C(S)NR₂₁NR₂₂R₂₃, where R₂₁,R₂₂, R₂₃, and R₂₄ are each independently H, an alkyl group, a cycloalkylgroup, a heterocycloalkyl group, an aryl group, a heteroaryl group, anacyl group, or a thioacyl group, or where any of two of R₂₁, R₂₂, R₂₃,and R₂₄, together with the atom(s) to which they are bonded, form aheterocycloalkyl group, provided that Z and Z₁ are not both H;

[0019] or Z₁ and R₁, together with the atoms to which they are bonded,form a cycloalkyl or heterocycloalkyl group, where Z₁ and R₁ are asdefined above except for moieties that cannot form the cycloalkyl orheterocycloalkyl group;

[0020] or Z and Z₁, together with the atoms to which they are bonded,form a cycloalkyl or heterocycloalkyl group, where Z and Z′ are asdefined above except for moieties that cannot form the cycloalkyl orheterocycloalkyl group.

[0021] As discussed below, these antipicornaviral agents of formula Imay be synthesized by subjecting a compound of general formula IItogether with a compound of general formula III to a suitableamide-forming reaction. The process of the present invention, not onlyreduces the number of steps required to synthesize the compounds offormula III, but more importantly, it also employs less expensivestarting materials and reagents.

[0022] These objects, advantages and features of the present inventionwill be more fully understood and appreciated by reference to thewritten specification.

DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT OF THE INVENTION

[0023] As used in the present application, the following definitionsapply:

[0024] In accordance with a convention used in the art,

[0025] is used in structural formulas herein to depict the bond that isthe point of attachment of the moiety or substituent to the core orbackbone structure.

[0026] Where chiral carbons are included in chemical structures, unlessa particular orientation is depicted, both sterioisomeric forms areintended to be encompassed.

[0027] An “alkyl group” is intended to mean a straight or branched chainmonovalent radical of saturated and/or unsaturated carbon atoms andhydrogen atoms, such as methyl (Me), ethyl (Et), propyl, isopropyl,butyl (Bu), isobutyl, t-butyl (t-Bu), ethenyl, pentenyl, butenyl,propenyl, ethynyl, butynyl, propynyl, pentynyl, hexynyl, and the like,which may be unsubstituted (i.e., containing only carbon and hydrogen)or substituted by one or more suitable sustituents as defined below(e.g., one or more halogens, such as F, Cl, Br, or I, with F and Clbeing prefered). A “lower alkyl group” is intended to mean an alkylgroup having from 1 to 4 carbon atoms in its chain.

[0028] A “cycloalkyl group” is intended to mean a non-aromaticmonovalent monocyclic, bicyclic, or tricyclic radical containing 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon ring atoms, each of whichmay be saturated or unsaturated, and which may be unsubstituted orsubstituted by one or more suitable substituents as defined below, andto which may be fused one or more heterocycloalkyl groups, aryl groups,or heteroaryl groups, which themselves may be unsubstituted orsubstituted by one or more substituents. Illustrative examples ofcycloalkyl groups include the the following moieties:

[0029] A “heterocycloalky group” is intended to mean a non-aromaticmonovalent monocyclic, bicyclic, or tricyclic radical, which issaturated or unsaturated, containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, or 18 ring atoms, which includes 1, 2, 3, 4, or 5heteroatoms selected nitrogen, oxygen, and sulfur, where the radical isunsubstituted or substituted by one or more suitable substituents asdefined below, and to which may be fused one or more cycloalkyl groups,aryl groups, or heteroaryl groups, which themselves may be unsubstitutedor substituted by one or more suitable substituents. Illustrativeexamples of heterocycloalkyl groups include the following moieties:

[0030] An “aryl group” is intended to mean an aromatic monovalentmonocyclic, bicyclic, or tricyclic radical containing 6, 10, 14 or 18carbon ring atoms, which may be unsubstituted or substituted by one ormore suitable substituents as defined below, and to which may be fusedone or more cycloalkyl groups, heterocycloalkyl groups, or heteroarylgroups, which themselves may be unsubstituted or substituted by one ormore suitable substituents. Illustrative examples of aryl groups includethe following moieties:

[0031] A “heteroaryl group” is intended to mean an aromatic monovalentmonocyclic,

[0032] bicyclic, or tricyclic radical containing 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, or 18 ring atoms, including 1, 2, 3, 4, or 5heteroatoms selected from nitrogen, oxygen, and sulfur, which may beunsubstituted or substituted by one or more suitable substituents asdefined below, and to which may be fused one or more cycloalkyl groups,heterocycloalkyl groups, or aryl groups, which themselves may beunsubstituted or substituted by one or more suitable substituents.Illustrative examples of heteroaryl groups include the followingmoieties:

[0033] A “heterocycle” is intended to mean a heteroaryl orheterocycloalkyl group (each of which, as defined above, are optionallysubstituted).

[0034] An “acyl group” is intended to mean a —(O)—R radical, where R isa substituent as defined below.

[0035] A “thioacyl group” is intended to mean a —(S)—R radical, where Ris a substituent as defined below.

[0036] A “sulfonyl group” is intended to mean a —SO₂R radical, where Ris a substituent as defined below.

[0037] A “hydroxy group” is intended to mean the radical —OH.

[0038] An “amino group” is intended to mean the radical —NH₂.

[0039] An “alkylamino group” is intended to mean the radical —NHR_(a),where R_(a) is an alkyl group.

[0040] A “dialkylamino group” is intended to mean the radical—NR_(a)R_(b), where R_(a) and R_(b) are each independently an alkylgroup.

[0041] An “alkoxy group” is intended to mean the radical —OR_(a), whereR_(a) is an alkyl group. Exemplary alkoxy groups include methoxy,ethoxy, propoxy, and the like.

[0042] An “alkoxycarbonyl group” is intended to mean the radical—C(O)OR_(a), where R_(a) is an alkyl group.

[0043] An “alkylsulfonyl group” is intended to mean the radical—SO₂R_(a), where R_(a) is an alkyl group.

[0044] An “alkylaminocarbonyl group” is intended to mean the radical—C(O)NHR_(a), where R_(a) is an alkyl group.

[0045] A “dialkylaminocarbonyl group” is intended to mean the radical—C(O)NR_(a)R_(b), where R_(a) and R_(b) are each independently an alkylgroup.

[0046] A “mercapto group” is intended to mean the radical —SH.

[0047] An “alkylthio group” is intended to mean the radical —SR_(a),where R_(a) is an alkyl group.

[0048] A “carboxy group” is intended to mean the radical —C(O)OH.

[0049] A “carbamoyl group” is intended to mean the radical —C(O)NH₂.

[0050] An “aryloxy group” is intended to mean the radical —OR_(c), whereR_(c) is an aryl group.

[0051] A “heteroaryloxy group” is intended to mean the radical —OR_(d),where R_(d) is a heteroaryl group.

[0052] An “arylthio group” is intended to mean the radical —SR_(c),where R_(c) is an aryl group.

[0053] A “heteroarylthio group” is intended to mean the radical —SR_(d),where R_(d) is a heteroaryl group.

[0054] A “leaving group” (Lv) is intended to mean any suitable groupthat will be displaced by a substitution reaction. One of ordinary skillin the art will know that any conjugate base of a strong acid can act asa leaving group. Illustrative examples of suitable leaving groupsinclude, but are not limited to, —F, —Cl, —Br, alkyl chlorides, alkylbromides, alkyl iodides, alkyl sulfonates, alkyl benzenesulfonates,alkyl p-toluenesulfonates, alkyl methanesulfonates, triflate, and anygroups having a bisulfate, methyl sulfate, or sulfonate ion.

[0055] Typical protecting groups, reagents and solvents such as, but notlimited to, those listed below in table 1 have the followingabbreviations as used herein and in the claims. One skilled in the artwould understand that the compounds listed within each group may be usedinterchangeably; for instance, a compound listed under “reagents andsolvents” may be used as a protecting group, and so on. Further, oneskilled in the art would know other possible protecting groups, reagentsand solvents; these are intended to be within the scope of thisinvention. TABLE 1 Protecting Groups Ada Adamantane acetyl AllocAllyloxycarbonyl Allyl Allyl ester Boc tert-butyloxycarbonyl Bzl BenzylCbz Benzyloxycarbonyl Fmoc Fluorenylmethyloxycarbonyl OBzl Benzyl esterOEt Ethyl ester OMe Methyl ester Tos (Tosyl) p-Toluenesulfonyl TrtTriphenylmethyl Reagents and Solvents ACN Acetonitrile AcOH Acetic acidAc.sub.2 O Acetic acid anhydride AdacOH Adamantane acetic acid AIBN2,2-azobisisobutyronitrile Alloc-Cl Allyloxycarbonyl chloride BHT2,6-di-tert-butyl-4-methylphenol Boc.sub.2 O Di-tert butyl dicarbonateCDI 1,1′-carbonyldiimidazole DIEA Diisopropylethylamine DIPEAN,N-diisopropylethylamine DMA Dimethylacetamide DMFN,N-dimethylformamide DMSO Dimethyl sulfoxide EDTAethylenediaminetetraacetic acid Et.sub.3 N Triethylamine EtOAc Ethylacetate FDH formate dehydrogenase FmocOSu 9-fluorenylmethyloxy carbonylN-hydroxysuccinimide ester HATU N-[(dimethylamino)-1H-1,2,3-triazol [4,5-b] pyridiyl- methylene]-N-methylmethanaminium hexafluorophosphateN-oxide HOBT 1-Hydroxybenzotriazole HF Hydrofluoric acid LDH lactatedehydrogenase LiHMDS Lithium bistrimethylsilylamide MeOH Methanol Mes(Mesyl) Methanesulfonyl MTBE t-butyl methyl ether NAD Nicotinamideadenine dinucleotide NADH Hydrogen-peroxide oxidoreductase NaHMDS Sodiumbistrimethylsilylamide NMP 1-methyl-2-pyrrolidinone nin. Ninhydrini-PrOH Iso-propanol Pip Piperidine PPL Lipase pTSA p-toluensulfonic acidmonohydrate Pyr Pyridine TEA Triethylamine TET triethylenetetraamine TFATrifluoroacetic acid THF Tetrahydrofuran Triflate (Tf)Trifluoromethanesulfonyl

[0056] The term “suitable organic moiety” is intended to mean anyorganic moiety recognizable, such as by routine testing, to thoseskilled in the art as not adversely affecting the inhibitory activity ofthe inventive compounds. Illustrative examples of suitable organicmoieties include, but are not limited to, hydroxyl groups, alkyl groups,oxo groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups,heteroaryl groups, acyl groups, sulfonyl groups, mercapto groups,alkylthio groups, alkoxy groups, carboxy groups, amino groups,alkylamino groups, dialkylamino groups, carbamoyl groups, arylthiogroups, heteroarylthio groups, and the like.

[0057] The term “substituent” or “suitable substituent” is intended tomean any suitable substituent that may be recognized or selected, suchas through routine testing, by those skilled in the art. Illustrativeexamples of suitable substituents include hydroxy groups, halogens, oxogroups, alkyl groups, acyl groups, sulfonyl groups, mercapto groups,alkylthio groups, alkyloxy groups, cycloalkyl groups, heterocycloalkylgroups, aryl groups, heteroaryl groups, carboxy groups, amino groups,alkylamino groups, dialkylamino groups, carbamoyl groups, aryloxygroups, heteroaryloxy groups, arylthio groups, heteroarylthio groups,and the like.

[0058] The term “optionally substituted” is intended to expresslyindicate that the specified group is unsubstituted or substituted by oneor more suitable substituents, unless the optional substituents areexpressly specified, in which case the term indicates that the group isunsubstituted or substituted with the specified substituents. As definedabove, various groups may be unsubstituted or substituted (i.e., theyare optionally substituted) unless indicated otherwise herein (e.g., byindicating that the specified group is unsubstituted).

[0059] A “prodrug” is intended to mean a compound that is convertedunder physiological conditions or by solvolysis or metabolically to aspecified compound that is pharmaceutically active.

[0060] A “pharmaceutically active metabolite” is intended to mean apharmacologically active product produced through metabolism in the bodyof a specified compound.

[0061] A “solvate” is intended to mean a pharmaceutically acceptablesolvate form of a specified compound that retains the biologicaleffectiveness of such compound. Examples of solvates include compoundsof the invention in combination with water, isopropanol, ethanol,methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.

[0062] A “pharmaceutically acceptable salt” is intended to mean a saltthat retains the biological effectiveness of the free acids and bases ofthe specified compound and that is not biologically or otherwiseundesirable. Examples of pharmaceutically acceptable salts includesulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophaosphates, chlorides, bromides, iodides, acetates, propionates,decanoates, caprylates, acrylates, formates, isobutyrates, caproates,heptanoates, propiolates, oxalates, malonates, succinates, suberates,sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates,benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,xylenesulfonates, phylacetates, phenylpropionates, phylbutyrates,citrates, lactates, γ-hydroxybutyrates, glycollates, tartrates,methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates,naphthalene-2-sulfonates, and mandelates.

[0063] The present invention further provides synthetic methods that arecomprised of one of the synthetic steps set forth in the presentdisclosure. A synthetic method is comprised of a synthetic step when thesynthetic step is at least part of the final synthetic method. In such afashion, the synthetic method can be only the synthetic step or haveadditional synthetic steps that may be associated with it. Such asynthetic method can have a few additional synthetic steps or can havenumerous additional synthetic steps.

[0064] If the antipicornaviral agent of formula I formed from theprocess of the present invention is a base, a desired salt may beprepared by any suitable method known to the art, including treatment ofthe free base with an inorganic acid, such as hydrochloric acid;hydrobromic acid; sulfuric acid; nitric acid; phosphoric acid; and thelike, or with an organic acid, such as acetic acid; maleic acid;succinic acid; mandelic acid; fumaric acid; malonic acid; pyruvic acid;oxalic acid; glycolic acid; salicylic acid; pyranosidyl acid, such asglucuronic acid or galacturonic acid; alpha-hydroxy acid, such as citricacid or tartaric acid; amino acid, such as aspartic acid or glutamicacid; aromatic acid, such as benzoic acid or cinnamic acid; sulfonicacid, such as p-toluenesulfonic acid or ethanesulfonic acid; or mistusesof acids or the like.

[0065] If the antipicornaviral agent of formula I formed from theprocess of the present invention is an acid, a desired salt may beprepared by any suitable method known to the art, including treatment ofthe free acid with an inorganic or organic base, such as an amine(primary, secondary, or tertiary); an alkali metal or alkaline earthmetal hydroxide; or the like. Illustrative examples of suitable saltsinclude organic salts derived from amino acids such as glycine andarginine; ammonia; primary, secondary, and tertiary amines; and cyclicamines, such as piperidine, morpholine, and piperazine; as well asinorganic salts derived from sodium, calcium, potassium, magnesium,manganese, iron, copper, zinc, aluminum, and lithium.

[0066] In the case of compounds, salts, or solvates that are solids, itis understood by those skilled in the art that the compounds of formulaI and the intermediates used in the process of the present invention,salts, and solvates thereof, may exist in different crystal forms, allof which are intended to be within the scope of the present inventionand specified formulas.

[0067] The antipicornaviral agents of formula I, and the intermediatesused in the process of the present invention, may exist as singlestereoisomers, racemates, and/or mixtures of enantiometers and/ordiastereomers. All such single stereoisomers, racemates, and mixturesthereof are intended to be within the broad scope of the presentinvention. Preferably, however, the intermediate compounds used in theprocess of the present invention are used in optically pure form.

[0068] As generally understood by those skilled in the art, an opticallypure compound is one that is enantiomerically pure. As used herein, theterm “optically pure” is intended to mean a compound comprising at leasta sufficient amount of a single enantiomer to yield a compound havingthe desired pharmacological activity. Preferably, “optically pure” isintended to mean a compound that comprises at least 90% of a singleisomer (80% enantiomeric excess (hereinafter “e.e.”)), more preferablyat least 95% (90% e.e.), even more preferably at least 97.5% (95% e.e.),and most preferably at least 99% (98% e.e.) Preferably, theantipicornaviral agents of formula I formed from the process of thepresent invention are optically pure.

[0069] The present invention relates to a process of preparingantipicornaviral agents of formula I:

[0070] wherein R₁ is H, F, an alkyl group, OH, SH, or an O-alkyl group;

[0071] R₂ and R₃ are each independently H;

[0072]  where n is an integer from 0 to 5, A₁ is CH or N, A₂ and each A₃are independently selected from C(R₄₁)(R₄₁), N(R₄₁), S, S(O), S(O)₂, andO, and A₄ is NH or NR₄₁, where each R₄₁ is independently H or loweralkyl, provided that no more than two heteroatoms occur consecutively inthe above-depicted ring formed by A₁, A₂, (A₃)_(n), A₄ and C═O, and atleast one of R₂ and R₃ is

[0073] R₅ and R₆ are each independently H, F, an alkyl group, acycloalkyl group, a heterocycloalkyl group, an aryl group, or aheteroaryl group;

[0074] R₇ and R₈ are each independently H, an alkyl group, a cycloalkylgroup, a heterocycloalkyl group, an aryl group, a heteroaryl group,—OR₁₇, —SR₁₇, —NR₁₇R₁₈, —NR₁₉NR₁₇R₁₈, or —NR₁₇R₁₈, where R₁₇, R₁₈, andR₁₉ are each independently H, an alkyl group, a cycloalkyl group, aheterocycloalkyl group, an aryl group, a heteroaryl group, or an acylgroup, provided that at least one of R₇ and R₈ is an alkyl group, anaryl group, a heteroaryl group, —OR₁₇, —SR₁₇, —NR₁₇R₁₈, —NR₁₉NR₁₇R₁₈, or—NR₁₇OR₁₈;

[0075] R₉ is a five-membered heterocycle having from one to threeheteroatoms selected from O, N, and S; and

[0076] Z and Z₁ are each independently H, F, an alkyl group, acycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroarylgroup, —C(O)R₂₁, —CO₂R₂₁, CN, —C(O)NR₂₁R₂₂, —C(O)NR₂₁OR₂₂, —C(S)R₂₁,—C(S)NR₂₁R₂₂, —NO₂, —SOR₂₁, —SO₂R₂₁, —SO₂NR₂₁R₂₂, —SO(NR₂₁)(OR₂₂),—SONR₂₁, —SO₃R₂₁, —PO(OR₂₁)₂, —PO(R₂₁)(R₂₂), —PO(NR₂₁R₂₂)(OR₂₃),—PO(NR₂₁R₂₂)(NR₂₃R₂₄), —C(O)NR₂₁NR₂₂R₂₃, or —C(S)NR₂₁NR₂₂R₂₃, where R₂₁,R₂₂, R₂₃, and R₂₄ are each independently H, an alkyl group, a cycloalkylgroup, a heterocycloalkyl group, an aryl group, a heteroaryl group, anacyl group, or a thioacyl group, or where any of two of R₂₁, R₂₂, R₂₃,and R₂₄, together with the atom(s) to which they are bonded, form aheterocycloalkyl group, provided that Z and Z₁ are not both H; or Z₁ andR₁, together with the atoms to which they are bonded, form a cycloalkylor heterocycloalkyl group, where Z₁ and R₁ are as defined above exceptfor moieties that cannot form the cycloalkyl or heterocycloalkyl group;

[0077] or Z and Z₁, together with the atoms to which they are bonded,form a cycloalkyl or heterocycloalkyl group, where Z and Z₁ are asdefined above except for moieties that cannot form the cycloalkyl orheterocycloalkyl group.

[0078] The present invention discloses that a compound of formula I maybe prepared by subjecting a compound of formula II and a compound offormula III to a amide-forming reaction:

[0079] The amide-forming reaction may be achieved by any suitablemethod, reagents and reaction conditions. Preferably, any one of themethods disclosed in the −354 application is utilized. For example, acompound of formula II may be reacted with a compound of formula III inthe presence of HATU, DIPEA, CH₃CN and H₂O to yield desired compound offormula I. Any suitable purification method may be used to furtherpurify the compound of formula I.

[0080] More preferably, the compound of formula I is prepared by anamide-forming reaction comprising the steps of:

[0081] (a) reacting the compound of formula II with a compound offormula IIIA in the presence of N-methylmorpholine to form a reactionmixture; and

[0082] (b) adding a compound of formula Lv—X to the reaction mixture toform a compound of formula I, wherein X is any suitable halide.

[0083] Preferably, the method for preparing the compound of formula Iutilizing the more preferable amide-forming reaction utilizes some orall of the reagents and reaction conditions disclosed below. Thus,preferably, the compound of formula II and the compound of formula IIIAin DMF are combined in any suitable container. The suitable container ispreferably a single neck flask which is then covered with any suitableseptum and covered with a temperature probe. Nitrogen gas is used topurge out the suitable container before N-methylmorpholine is added tothe reaction mixture. More preferably, the N-methylmorpholine is addedvia a syringe in one single portion and the reaction mixture cooled toabout between —5° C. and 5° C. More preferably, the reaction mixture iscooled to about 0° C. A solution of the compound of formula Lv—X is thenadded to the reaction mixture. More preferably, the solution of thecompound of formula Lv—X is a solution of the compound of formula Lv—Xin DMF. Even more preferably, the compound of formula Lv—X is CDMT. Thesolution of the compound of formula Lv—X is added to the reactionmixture by any suitable method so as to maintain the reaction mixture ata constant temperature. For example, the solution of the compound offormula Lv—X may be added to the reaction mixture dropwise utilizing asyringe. Upon completion of the addition of the solution of the compoundof formula Lv—X, the reaction mixture is allowed to warm to about roomtemperature. The progress of the reaction may be followed by monitoringthe disappearance of the compound of formula II by thin layerchromatography (hereinafter “TLC”). When the reaction is at leastsubstantially complete, the compound of formula I may be precipitatedout of solution to form a slurry by slowly adding water to the reactionmixture. The compound of formula I may then be removed from the slurryby any suitable means known to one of ordinary skill in the art. Forexample, the compound compound of formula V. Preferably, the methoddisclosed in U.S. patent application Ser. No. 08/991,739 is used. U.S.patent application Ser. No. 08/991,739 is herein incorporated byreference in its entirety.

[0084] The process of the present invention comprises the steps of:

[0085] (a) cyanomethylation of the compound of formula V usingbis(trimethysilyl)amide and bromoacetonitrile to yield a compound offormula VI;

[0086] of formula I may be removed from the slurry by filtration. Anysuitable purification method known to one of ordinary skill in the artmay be used to purify the compound of formula I. More preferably, thecompound of formula I is purified by recrystalization.

[0087] The present invention also discloses two alternate processes forthe synthesis of the compound of formula III and acid addition saltsthereof. Of these two routes, the second process is currently preferredbecause it offers greater cost-effectiveness at a commercial scale.

[0088] The first of these two processes is for the preparation of acompound of formula IV and its acid addition salts from a compound offormula V.

[0089] One of ordinary skill will recognize that the compounds offormula IV are a subgenus to those of formula III.

[0090] The compound of formula V may be prepared from commerciallyavailable N-Boc L glutanic acid γ-benzyl ester. Any suitable method maybe used to prepare the

[0091] (b) the reduction, cyclization, and deprotection of the compoundof formula VI in that respective order to yield a compound of formulaVII; and

[0092] (c) the oxidation and olefination of the compound of formula VIIby reacting the compound with a SO₃-pyridine complex to yield a reactionmixture and reacting the reaction mixture with a phosphorane of formulaVIII.

[0093] According to the present invention, and as disclosed above, thepreparation of the compound of formula V from N-Boc glutanic acidγ-benzyl ester may be carried out by any suitable method known in theart.

[0094] Further, the cyanomethylation of the compound of formula V may becarried out using any suitable method, reagents and reaction conditions.Preferably, the method disclosed below and the use of all or some of thereagents and reaction conditions are used. Thus, it is preferable, thatthe compound of formula V be added dropwise to a stirring solution ofNaHMDS in THF at −70° C. in a nitrogen atmosphere over a period of atleast about 5 hours before being mixed with bromoacetonitrile.

[0095] This cyanomethylation of the compound of formula V usingbis(trimethylsilyl)amide and bromoacetonitrile affords the compound offormula VI along with its epimer in a 5:1 ratio. However, the compoundmay be purified by any suitable method. Preferably, the compound offormula VI is purified by filtration and chromatography, followed bytitration. Under these preferred conditions, a 60% overall yield of thecompound of formula VI is attainable having >99% diastereomeric purity.

[0096] The three step reduction, cyclization, and deprotection reactionof step (b) to convert the compound of formula VI to the compound offormula VII may be carried out using any suitable reagents and reactionconditions. Preferably, the method disclosed below, using all or some ofthe reagents and reaction conditions are used. Therefore, preferably,the compound of formula VI is reduced by adding a solution of cobalt(II) chloride hexahydrate to a solution of the compound of formula VI intetrahydrofuran in methanol. The resulting solution is cooled to aboutO° C. before sodium borohydride is added in portions over a period of atleast about 7 hours. Then, p-toluensulfonic acid monohydrate is added tothe solution of crude material in methanol and allowed to react for atleast about 18 hours at an ambient temperature. After removal of thesolvent, the residue is dissolved in ethyl acetate and washed. Anysuitable washing agent may be used. More preferably, the washing agentis saturated sodium bicarbonate. The crude product is then charged witha solution of methanol in water. More preferably, a 2.5% methanolsolution is used. The crude product may be removed from solution by anysuitable method. For example, the crude product may be removed byfiltration and the filtrate concentrated on a rotary evaporator. Theproduct is then dissolved in ethyl acetate, dried, filtered andconcentrated to the crude compound of formula VII. More preferably, theproduct is dried over MgSO₄. The crude compound of formula VII may befurther purified by any suitable purification process. More preferably,the crude compound of formula VII is purified through a titrationprocess using 1:1 ethyl acetate and hexanes.

[0097] An overall yield of at least about 95% pure compound of formulaVII is attainable if the preferred three step reduction, cyclization,and deprotection reaction disclosed above is used.

[0098] Any suitable method, reagents and reaction conditions may be usedin the subsequent oxidation and olefination employing a SO₃-pyridinecomplex and the phosphorane of formula VIII to yield the compound offormula IV. Preferably, the method disclosed below and all or some ofthe reagents and reaction conditions are used. Accordingly, preferably,triethylamine is added to a solution of the compound of formula VIII andmethylsulfoxide. The resulting solution is cooled to about 5° C.,followed by the addition of a sulfur trioxide-pyridine complex. Thereaction is stirred at about 5° C. for at least about 15 minutes. Afterremoving the source used to cool the solution to about 5° C., thereaction is stirred for at least about an additional 1 hour.(Carboethoxymethylenetriphenyl)-phosphorane is then added and thereaction mixture stirred at ambient temperature for at least about 3hours. Then, the reaction is quenched and extracted with ethyl acetate.More preferably, the reaction is quenched by the addition of saturatedbrine. The combined organic phases are then washed, dried, filtered andconcentrated to afford crude compound of formula IV. More preferably,the combined organic phases are washed with saturated brine and driedover MgSO₄.

[0099] The compound of formula IV may be purified by any suitablemethod. Preferably, chromatography purification and titration techniquesare used. If the preferable purification technique is used, yieldsranging from 55% to 60% are attainable.

[0100] The second process for preparing the compound of formula IV, andits acid addition salts, disclosed by the present invention comprisesthe steps of:

[0101] (a) the dianionic alkylation of a compound of formula IX usingbromoacetonitrile to yield a compound of formula X;

[0102] (b) hydrogenation of the compound of formula X to yield an amineof formula XI;

[0103] (c) reacting the amine formula XI with ET₃N to yield a lactamester of formula XII;

[0104] (d) the reduction of the lactam ester of formula XII through asuitable reduction

[0105]  procedure to yield a compound of formula XIII;

[0106] (e) the oxidation and olefination of the compound of formula XIIIto yield a compound of formula XIV by reacting it with a compound offormula XV; and

[0107] (f) converting the compound of formula XIV to the compound offormula IV.

[0108] Further, one of ordinary skill in the art will realize that theabove disclosed method may be used to prepare the compound of formulaXIV. Specifically, steps (a)-(e) disclose a process for preparing thecompound of formula XIV.

[0109] The compound of formula IX may be prepared by any suitable methodknown in the art. For example, N-Boc L-(+)-glutamic acid dimethyl estermay be prepared from commercially available L-glutamic acid dimethylester hydrochloride or commercially available L-glutamic acid 5-methylester according to literature procedures. See for example, Shimamoto etal, J. Org. Chem. 1991, 56, 4167 and Duralski et al, Tetrahedron Lett.1998, 30, 3585. These references are herein incorporated by reference intheir entirety.

[0110] Preferably, the dianionic alkylation reaction is performed usingthe method and all or some of the reagents and reaction conditionsdisclosed below. Therefore, preferably, the compound of formula IX isfirst dissolved in THF to form a solution which is added dropwise to astirring solution of LiHMDS at −78° C. in an Argon atmosphere. Theresulting mixture is then stirred at about −78° C. for 2 hours beforefreshly distilled bromoacetonitrile is added dropwise over a period of 1hour. The reaction mixture is stirred at about −78° C. for additional 2hours. The reaction is then quenched. More preferably, the reaction isquenched by adding 0.5 M HCl and H₂O. The resulting aqueous layer isseparated and is extracted further with methyl tert-butyl ether. Thecombined organic extract is washed, dried and filtered. More preferably,the organic extract is washed with saturated NaHCO₃ and brine and driedover MgSO₄. The solvent is evaporated under reduced pressure

[0111] The compound of formula IX may be hydrogenated to the amine offormula XI by any suitable method known in the art. Preferably, thehydrogenation is performed in the presence of 5% Pd/C. More preferably,the hydrogenation reaction is performed in accordance with the method,using some or all of the reagents and reaction conditions disclosedbelow. According to this preferred hydrogenation method, the compound offormula IX is dissolved in HOAc and shaken with 5% Pd on C under H₂ gas,at 50 psi pressure, for 3 days. The mixture is then filtered overcelite. The filtrate may then be evaporated under reduced pressure andthe residue repeatedly evaporated from methyl tert-butyl ether.

[0112] Alternatively, in a preferred method the compound of formula Xmay be hydrogenated to the amine of formula XI by hydrogenating compoundX in the presence of PtO₂. More preferably, the hydrogenation reactionis performed in accordance with the method, using some or all of thereagents and reaction conditions disclosed below. Although the acetatesalt of amine XI is shown, any strong acid can be used to form anacceptable salt. Examples of strong acids would include hydrochloric,hydrobromic, acetic, formic, sulfuric and propanoic acids. Preferablythe salt of the amine base of formula XI can be the acetate or chloridesalt and more preferably the chloride salt is used.

[0113] The reaction of the amine salt of formula XI with any strong basewill yield the lactam ester of formula XII. Examples of strong basesinclude Et₃N, Na₂CO₃, NaOH, Pr₃N, K₂CO₃, and KOH. Preferred strong basesare Et₃N, Na₂CO₃ and K₂CO₃.

[0114] The reaction of the amine of formula XI with Et₃N may be achievedusing any suitable conditions. Preferably, the method and all or some ofthe reagents and reaction conditions disclosed below are used.Accordingly, preferably, the amine of formula XI is dissolved in 1:1MeOH/THF, before Et₃N is added to the solution. The resulting mixture isstirred at about 45° C. for about 10 hours or until the startingmaterial has disappeared. The presence of the starting material may bemonitored by ¹H NMR. After stripping off the solvent, methyl tert-butylether is added. The precipitate is then filtered. 0.5 M HCl is added tothe filtrate diluted with H₂O . After splitting the phases, the aqueousphase may be extracted with ethyl acetate. The combined organic phasesare washed, dried, filtered and concentrated. More preferably, thecombined organic phases are washed with brine and dried over MgSO₄. Thephases may be concentrated on a rotovapor. Flash chromatography famishesthe lactam ester of formula XII.

[0115] Any suitable reduction method may be used to convert the lactamester of formula XII to the compound of formula XIII. Preferably, LiBH₄is used as the reducing agent. More preferably, the method, or anyportion thereof, and any or all of the reagents and reaction conditionsdisclosed below are used. Thus, more preferably, LiBH₄ is added to astirring solution of the lactam ester of formula XII in THF. The LiBH₄is added in several portions at 0° C. in an Argon atmosphere. Thereaction mixture is stirred at 0° C. for 10 minutes, before beingallowed to warm to ambient temperature and stirred for an additional 2hours. Then, the reaction is quenched. Even more preferably, thereaction is quenched by the dropwise addition of 0.5 M HCl while coolingusing an ice bath. The solution is diluted with ethyl acetate and H₂O.After splitting the phases, the aqueous phase may be extracted withethyl acetate. The combined organic phases are washed, dried, filteredand concentrated. Even more preferably, the combined organic phases arewashed with brine and dried over MgSO₄. The phases may be concentratedon a rotovapor. Flash chromatography furnishes the compound of formulaXII.

[0116] Any suitable oxidation and olefination method may be used toprepare the compound of formula XIV from the compound of formula XIII.Preferably, the method, or any part thereof, and all or some of thereagents and reaction conditions described below are used. Thus, inaccordance with the present invention, benzoic acid,(carboethoxymethylenetriphenyl)phosphorane and DMSO are added to asolution of the compound of formula XIII in CH₂Cl₂. Dess-Martinperiodinane is added to the solution in several portions, and thereaction mixture is then stirred for at least about 5 hours at ambienttemperature until the compound of formula XIII substantially disappears.The presence of the compound of formula XIII may be monitored by ¹H NMR.Saturated NaHCO₃ solution is added before the mixture is stirred for 30minutes to yield a precipitate. The precipitate is filtered prior to theorganic phase of the filtrate being separated, washed, and concentratedto yield the crude compound of formula XIV. More preferably, thefiltrate is washed with brine and concentrated on a rotovapor. Anysuitable method may be used to purify the crude compound of formula XIV.More preferably, the crude compound of formula XIV is purified by flashchromatography, then dissolved in ethyl acetate. Excess hexanes are thenadded gradually to the stirring solution to yield a precipitated. Theprecipitate is filtered and dried to afford the compound of formula XIV.More preferably, the precipitate is dried in a vacuum oven for at leastabout 12 hours.

[0117] The following examples are provided merely for illustrativepurposes of the present invention and are not to be read as limiting thescope of protection of the present invention, as defined by the appendedclaims.

EXAMPLES

[0118] The following illustrates an example of the amide-formingreaction between two compounds falling within the scope of formulae IIand III to prepare a compound falling within the scope of formula I.Specifically, this example, as depicted in Scheme I below, illustratesthe reaction of 1 with 2 to prepare the protease inhibitorethyl-3-{(5′-methylisoxazole-3′-carbonyl)-L-ValΨ(COCH₂)-L-(4-F-Phe)-L-((S)-Pyrrol-Ala)}-E-propanoate.

[0119] The following examples disclose the preparation of compound 1falling within the scope of formula IV. The first example, as depictedin Scheme 2 below, illustrates the use of the cyanomethylation routedisclosed above. The second example, depicted in Scheme 3 below,illustrates the second more preferable cost effective route forpreparing the same compound.

[0120] Preparation of 4 (Scheme 2)

[0121] A solution of 3 (1.0 kg, 2.34 mol, 1.0 equiv.) in THF (8.0 L) wasadded dropwise to a stirring solution of NaHMDS in THF (1M in THF, 2.96L, 1.28 equiv.) at −70° C. in a nitrogen atmosphere over a period of 5hours. The resulting solution was stirred at −70° C. for 0.5 hours andfreshly distilled bromoacetonitrile (320 mL, 2.0 equiv.) was then addeddropwise over a period of 25 minutes. The reaction mixture was stirredat −70° C. for additional 1 hour until the disappearance of the startingmaterial 3. The reaction was quenched by addition of saturated ammoniumchloride solution (7.0 L), and extracted with methyl tert-butyl ether(24 L). The organic phase was washed with brine (3×6.0 L). The solventwas removed under reduce pressure to afford a dark brown oil (1.5 kg).This crude product was dissolved in methylene chloride (8.0 L) andpassed over a bed of silical gel (600 g) and activated carbon (250 g).After rinsing the cake with methylene chloride (4.0 L), the filtrate wasconcentrated on a rotary evaporator to afford a light brown oil (1,28Kg), which was then dissolved in ethyl acetate (2.5 L). To the resultingsolution, excess hexanes (14.5 L) were added under vigorous stirring anda white solid precipitated out in 30 minutes. The slurry was cooled withan ice-water bath and stirred for 4.5 hours, followed by filtration toafford 4 as a light brown solid (662 g, 60%): ¹H NMR (CDCl₃) δ 1.46 (s,3H), 1.49 (s, 9H), 1.59 (s, 3H), 1.75-1.95 (m, 1H), 2.15-2.31 (m, 1H),2.55-3.15 (m, 3H), 3.36 (d, J=10.8 Hz, 1H), 3.62-4.10 (m, 3H), 4.13-4.32(m, 3H), 4.70 (m, 1H), 7.15-7.42 (m, 5H).

[0122] Preparation of 6 (Scheme 3)

[0123] Compound 6 was prepared from L-glutamic acid dimethyl esterhydrochloride (commercially available from Lancaster) or L-glutamic acid5-methyl ester (commercially available from Aldrich) according toliterature procedures.

[0124] Preparation of 7 (Scheme 4)

[0125] A solution of N-Boc L-(+)-glutamic acid dimethyl ester (5, 600 g,2.18 mole, 1 equiv.) in THF (6.0 L) was added dropwise to a solution ofLiHMDS in THF (4.7 L, 1M, 4.7 mol, 2.16 equiv.) at −78° C. in an Aratmosphere. The resulting dark mixture was stirred at −78° C. for 1 h.at the same time; bromoacetonitrile (400 g) was stirred with basicaluminum oxide (70 g) for 2 h and then filtered. The freshly filteredbromoacetonitrile (280 g, 2.33 mol, 1.07 equiv.) was added dropwise tothe dianion solution over a period of 1 h while maintaining thetemperature below —70° C. the reaction mixture was stirred at −78° C.for additional 1-2 h and the disappearance of the starting material (5)was confirmed by TLC analysis. The reaction was quenched with pre-cooledmethanol (300 ml) in one portion and stirred for 30 minutes. Theresulting methoxide was then quenched with a pre-cooled acetic acid inTHF solution (270 ml HOAc/2 L THF) in one portion. After stirring for 30minutes, the cooling bath was removed and replaced with a water bath.The reaction mixture was allowed to warm to 0±5° C. and then poured intoa brine solution (250 g of NaCl in 4 L of water) in a 50 L extractor.The layers were separated, and the organic layer was concentrated toafford a dark brown oil (˜850 g). Silica gel (800 g), activated carbon(200 g) and methylene chloride (2 L) were added to the Rotovap flask andspun on a Rotovap for 1 h without hear and vacuum. The slurry was thenfiltered and washed with another 2 L of methylene chloride. The lightbrown filtrate was concentrated to afford a light brown oil (7, 620 g,1.97 mole, 90% crude yield). The crude product, 7, was used in the nextstep without any further purification.

[0126] Preparation of 7 (Scheme 3)

[0127] A solution of N-Boc L-(+)-glutamic acid dimethyl ester (6, 10 g,36.3 mmol, 1 equiv.) in THF (100 mL) was added dropwise to a stirringsolution of LiHMDS (77 mL, 1M in THF, 77.0 mmol, 2.1 equiv.) at −78° C.in an Ar atmosphere. The resulting dark mixture was stirred at −78° C.for 2 hours, and then freshly distilled bromoacetonitrile (13.1 g, 109.0mmol, 3 equiv.) was added dropwise over a period of 1 hour. The reactionmixture was stirred at −78° C. for additional 2 hours and thedisappearance of the starting material (6) was confirmed by TLCanalysis. The reaction was quenched by addition of HCl (120 mL, 0.5 M)and H₂O (200 mL). The layers were separated, and the aqueous layer wasfurther extracted with methyl tert-butyl ether (3×200 mL). The combinedorganic extract was washed with saturated NaHCO₃ (2×250 mL), brine(2×250 mL), dried over MgSO₄ and filtered. The solvent was evaporatedunder reduce pressure to give a brown oil (15.2 g). Flash chromatographyover silica gel (3 1 hexanes/ethyl acetate) afforded a colorless oil (7,6.67 g, 10.8 mmol, 58%): H NMR (CDCl₃) δ 1.46 (s, 9H), 2.12-2.24 (m,2H), 2.77-2.82 (m, 2H), 2.85-2.91 (m, 1H), 3.78 (s, 3H), 3.79 (s, 3H),4.32-4.49 (m, 1H), 5.13 (d, J=6.0 Hz, 1H); ¹³C NMR (CDCl₃) δ 19.4, 28.6,34.3, 38.6, 49.8, 53.1, 80.9, 117.5, 155.9, 172.4, 172.8; HRMS /Z314.1481 (calculated for C₁₂H₂₂N₂O₄, 314.1486).

[0128] Preparation of 8 (Scheme 3)

[0129] Compound 7 (4.60 g, 14.6 mmol) was dissolved in HOAc (120 mL) andshaken with 5% Pd on C (20 g) under H₂ gas (50 psi) for 3 days. Themixture was filtered over Celite. The filtrate was evaporated underreduced pressure and the residue was repeatedly evaporated from methyltert-butyl ether to yield a light pink solid (8, 8.32 g), which was useddirectly in the next step. ¹H NMR (CD₃OD) δ 1.47 (s, 9H), 1.85-2.10 (m,4H), 2.60-2.62 (m, 1H), 2.92-2.96 (m, 2H), 3.74 (s, 3H), 3.77 (s, 3H),4.22-4.26 (m, 1H); Note: Experiments have demonstrated that less 5% Pdon C can drive the reaction to completion, i.e., 1 g of 5% Pd on C wasefficient for the reduction of 2 g of 7.

[0130] Preparation of 9 (Scheme 3)

[0131] Crude 8 was dissolved in 1:1 MeOH/THF (40 mL) and Et₃N (7 mL) wasadded to the solution. The resulting mixture was stirred at 45° C. for10 hours until the disappearance of the starting material monitored by¹H NMR. After stripping off the solvent on a rotovapor, methyltert-butyl ether (200 mL) was added and a white solid precipitated out.The solid precipitate was removed by filtration. The filtrate wasdiluted with 200 mL of H₂O followed by addition of 0.5 M HCl (5 mL). Thephases were split, and the aqueous phase was extracted with ethylacetate (4×200 mL). The combined organic phases were washed with brine(2×700 mL), dried over MgSO₄, filtered and concentrated on a rotovaporto give a light brown oil. Flash chromatography furnished a white solid(9, 2.5 g, 8.74 mmol, 60%): ¹H NMR (CDCl₃) δ 1.37 (s, 9H), 1.75-1.80 (m,2H), 2.04-2.09 (m, 1H), 2.39-2.42 (m, 2H), 3.25-3.29 (m, 2H), 3.67 (s,3H), 4.23-4.26 (m, 1H), 5.47 (d, J=8.0 Hz, 1H), 6.29 (s, 1H); ¹³C NMR(CDCl₃) δ 28.5. 28.6, 34.5, 38.5, 40.7, 52.7, 52.8, 80.3, 156.1, 173.3,180.0; HRMS m/z 286.1564 (calculated for C₁₃H₂₂N₂O₅, 286.1587).

[0132] Preparation of 9 (Scheme 4)

[0133] Crude 7 (628 g, 2.0 mole, 1.0 equiv.), methanol (5.6 L) andchloroform (0.56 L) was charged into a 19 L hydrogenator, followed bythe addition of platinum oxide (PtO₂, 30 g, 0.132 mole, 0.66 equiv.).The contents in the hydrogenator were pressurized to 50 psi withhydrogen and the reaction was monitored by HPLC until the disappearanceof 7 was confirmed. The suspension was then filtered through a pad ofCelite (®545 and washed with methanol (500 ml). To the resultingsolution of 8b was added sodium carbonate (100 g). The suspension washeated at 60° C. for 4-5 h until HPLC data confirmed the disappearanceof 8b and the formation of 9. The mixture was then concentrated underreduced pressure. The resulting oil was dissolved in ethyl acetate (4 L)and water (1.5 L). The ethyl acetate layer was isolated, and the aqueouslayer was extracted with ethyl acetate (2 L) and concentrated underreduced pressure. The crude product was further purified through a plugcolumn to afford 9 as a white solid (250 g, 0.874 mole, 40% overallyield from 6).

[0134] Preparation of 5 from 4 (Scheme 2)

[0135] To a solution of 4 (400 g, 0.85 mol, 1 equiv.) in tetrahydrofuran(3.0 L) was added a solution of cobalt (II) chloride hexahydrate (200 g,0.85 mol, 1 equiv.) in methanol (3.0 L). The resulting solution wascooled to 0° C. and sodium borohydride (130 g, 3.51 mol, 4.4 equiv.) wasadded in portions over a period of 7 hours. The reaction mixture wasallowed to warm to ambient temperature and stirred for 20 hours whilebeing monitored by TLC for the disappearance of the starting material(4). The reaction was cooled to 0° C. and quenched by addition of 1.0 MHCl (14 L) and ethyl acetate (12 L). The phases were separated and theaqueous phase was charged with 2.0 kg of sodium chloride and 4.0 L ofethyl acetate. The phases were separated, and the organic phases werecombined, washed with brine (1×3.0 L), concentrated on a rotaryevaporator to afford a crude material (440 g), which was used directlyin the following hydrolysis reaction. To a solution of the crudematerial (440 g, 1 equiv.) in methanol (800 mL) was addedp-toluensulfonic acid monohydrate (4.0 g, 0.015 equiv.). The reactionwas stirred at ambient temperature overnight. The solvent was removed ona rotary evaporator and the residue was dissolved in ethyl acetate (2.0L), washed with saturated sodium bicarbonate (2×100 mL). The combinedaqueous phases were extracted with ethyl acetate (2×200 mL). All theorganic phases were combined, concentrated on a rotary evaporator toafford 275 g of the crude product, which was charged with a solution of2.5% methanol (20 mL) in water (780 mL) and stirred at ambienttemperature overnight. The granular solid (chiral auxiliary) was removedby filtration and the filtrate was concentrated on a rotary evaporator.The residue was dissolved in ethyl acetate (1.5L), dried over MgSO₄,filtered and concentrated to afford a viscous oil. The oil was fartherpurified through a titration process using 1:1 ethyl acetate (1 L) andhexanes (1 L) to afford 5 as a white solid (104 g, 47% overall yieldfrom 4).

[0136] Preparation of 5 from 9 (Scheme 3)

[0137] To a stirring solution of 9 (1.75 g, 6.10 mmol) in THF (40 mL)was added LiBH₄ (270 mg, 12.2 mmol, 2 equiv.) in several portions at 0°C. in an Argon atmosphere. The reaction mixture was stirred at 0° C. for10 minutes, then allowed to warm to ambient temperature and stirred foradditional 2 hours. The reaction was quenched by the dropwise additionof 0.5 M HCl (24 mL) with cooling in an ice bath (Note: formation ofgases was observed). The solution was diluted with ethyl acetate (100mL) and H₂O (50 mL). The phases were split, and the aqueous layer wasextracted with ethyl acetate (6×150 mL). The combined organic phaseswere dried over MgSO₄, filtered and concentrated on rotovapor to give alight brown oil. Flash chromatography afforded a white solid (5, 1.308g, 5.06 mmol, 83%): ¹H NMR (CDCl₃) δ 1.46 (s, 9H), 1.61-1.67 (m, 1H),1.82-1.91 (m, 1H), 1.94-2.00 (m, 1H), 2.43-2.48 (m, 1H), 2.49-2.55 (m,1H), 3.32-3.34 (m, 3H), 3.58-3.66 (m, 2H), 3.68-3.79 (m, 2H), 5.47 (d,J=7.0 Hz, 1H), 6.24 (s, 1H); ¹³C NMR (CDCl₃) δ 28.8, 32.9, 38.4, 40.8,51.5, 66.3, 79.8, 157.0, 181.3; HRMS m/z 258.1652 (calculated forC₁₃H₂₂N₂O₅, 258.1650).

[0138] Preparation of 5 from 9 (Scheme 4)

[0139] To a stirring solution of 9 (2.42 Kg, 8.45 mole, 1.0 equiv.) inTHF (14 L) was added NaBH₄ (400 g, 10.6 mole, 1.25 equiv.) in severalportions at 5° C. in a nitrogen atmosphere. The reaction mixture wasstirred at 5° C. for 15 minutes, then methanol was added dropwise over aperiod of 1-2 h while keeping the reaction temperature below 30° C. Themixture was allowed to warm to ambient temperature and stirredovernight. The reaction was quenched by the addition of brine (6.0 L),followed by 20% aqueous citric acid solution (10.0 L). The mixture wasconcentrated under reduced pressure to remove THF and methanol. Theresulting aqueous solution was 15 extracted with methylene chloride(4×16 L). The combined methylene chloride extracts were concentratedunder reduced pressure to remove two thirds of the methylene chloride.Excess hexanes (16 L) were added and the resulting slurry was stirredfor 1 h, then filtered and dried to afford 5 (2.16 Kg, 7.58 mole, 89%).

[0140] Preparation of 1 from 5

[0141] Procedure A (Scheme 2)

[0142] To a solution of 5 (50.0 g, 0.184 mol, 1 equiv.) methylsulfoxide(500 mL) was added triethylamine (116 mL). The resulting solution wascooled to 5° C. with an ice bath, followed by addition of sulfurtrioxide-pyridine complex (132 g). The reaction was stirred at thattemperature for 15 min. The cold bath was removed and the reaction wasstirred for additional 1 hour.(Carboethoxymethylenetriphenyl)-phosphorane (112 g) was added in one lotand the reaction was stirred at ambient temperature for 3 hours. Thereaction was quenched by addition of saturated brine (3.0 L), extractedwith ethyl acetate (3×1.5 L). The combined organic phases were washedwith saturated brine (3×1.5 L), dried over MgSO₄, filtered andconcentrated to afford a dark red oil. The oil was purified through achromatography, followed by a titration process using ethyl acetate (60mL) and excess of hexanes (240 mL). 1 was obtained as a white solid(36.0 g, 60%). Procedure B (Scheme 3) To a solution of 5 (1.0 g, 3.87mmol, 1 equiv.) in CH₂Cl₂ (80 mL) was added benzoic acid (1.89 g, 15.5mmol., 4 equiv.), (carboethoxymethylenetriphenyl)phosphorane (5.39g,15.5 mmol, 4 equiv.) and DMSO (4.8 mL). Dess-Martin periodinane (4.1 g,9.17 mmol, 2.5 equiv.) was added in several portions to the solution,and the reaction mixture was then stirred for 5 hours at ambienttemperature until the disappearance of the starting material 5.Saturated NaHCO₃ solution was added, and the mixture was stirred for 30minutes. A white solid precipitated out, which was then filtered off.The organic phase of the filtrate was separated, washed with brine (250mL), and concentrated on rotovapor to give a brown oil, which waspurified by flash chromatography to produce a light brown foam (0.956g). The foam was dissolved in ethyl acetate (3 mL). Excess hexanes (12mL) was added gradually to the stirring solution and a white solidprecipitated out. The solid was filtered and dried in vacuum ovenovernight to afford 1 (0. 69g, 2.11 mmol, 55%). Chiral HPLC: 97% pure,98% de and 100% E isomer, ¹H NMR (CDCl₃) δ 1.22 (t, J=7.2 Hz, 3H), 1.38(s, 9H), 1.53-1.58 (m, 1H), 1.66-1.84 (m, 1H), 1.85-2.00 (m, 1H),2.30-2.50 (m, 2H), 3.20-3.37 (m, 2H), 4.13 (q, J=7.2 Hz, 2H), 4.20-4.35(m, 1 H), 5.13 (d, J=7.5 Hz, 1H), 5.68 (s, 1H), 5.90 (dd, J=1.8, 15.6Hz, 1H), 6.80 (dd, J=5.1, 15.6 Hz, 1H); HRMS m/z 326.1846 (calculatedfor C₁₆H₂6N₂O₆, 326.1840).

[0143] Preparation of 1 from 5 (Scheme 4)

[0144] Pyridine sulfur trioxide complex (98.58 g, 0.619 mole, 2 equiv.),DMSO (110 ml) and pyrideine (50 ml) were charged into a 500 ml flask.The mixture was stirred at ambient temperature for 1 h. At the sametime, to a solution of triethylphosphine in THF (1M, 526 ml, 0.526 mole,1.7 equiv.) was added methylene chloride (320 mL) at 0° C., followed byethyl bromoacetate (45 ml, 0.403 mole, 1.3 equiv.). The resulting Wittigsolution was allowed to warm to ambient temperature and stirred for 2 h.To a solution of 5 (80 g, 0.3 10 mole, 1 equiv.) in DMSO (110 mL) andmethylene chloride (400 ml) was added diisopropylethylamine (189 ml)at-5° C., followed by the addition of the previously prepared solutionof pyridine sulfur trioxide complex. The reaction mixture was stirredfor 1 h at −5° C. before the Wittig solution was added. After agitationfor 2 h, additional diisopropylethylamine (27 mL) was added and themixture was stirred at −5° C. for 1 h. The reaction was then allowed towarm to ambient temperature and stirred overnight. The reaction mixturewas concentrated under reduced pressure. The residue was charged withethyl acetate (480 mL) at 0° C., followed by the addition of 20% aqueouscitric acid solution. The ethyl acetate layer was separated, and theaqueous citric acid solution. The ethyl acetate layer was separated, andthe aqueous layer was extracted with ethyl acetate (2×400 mL). Thecombined ethyl acetate extracts were washed with 20 aqueous citric acidsolution (400 ml), saturated aqueous sodium bicarbonate solution (400ml) and saturated aqueous sodium chloride solution (400 ml). The ethylacetate layer was dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The crude product was purified by atrituration process with ethyl acetate (100 ml) and hexanes (400 ml) toafford 1 (86.5 g, 0.265 mole, 85%).

[0145] Preparation of Compound from 1 and 2 (Scheme 1). 751 mg ofcompound 1 was dissolved in DCM (10 mL/g of 1) in a single neck roundbottom flask and cover with a septum. The flask was then purged withnitrogen followed by the addition of 1.4 mL TFA via syringe while thesolution was being stirred. The progress of the reaction was monitoredby TLC using 5% MeOH in DCM until after about 4 hours the startingmaterial disappeared. The solvent and excess TFA were removed undervacuum at pressure of <50 mTorr @45° C. The product, compound 1A, wasused immediately in the step set forth below.

[0146] Compounds 1A and 2 were dissolved in DMF (7 mL/g of 2) in asingle neck flask covered with a septum and fitted with a temperatureprobe. The flask was purged with nitrogen. The resulting solution wasdivided into two portions. In a first portion was added 1.6 mLn-methylmorpholine via syringe and cooled to 0° C.±5° C. In a secondportion of the solution 281 mg CDMT was dissolved. This CDMT solutionwas then added dropwise via syringe to the first portion of thesolution, maintaining the reaction temperature of 0° C.±5° C. Theresulting reaction mixture was then allowed to warm to room temperature.The reaction was monitored for about 1 hour by TLC (7:3:1hexanes:EtOAc:IPA) until the compound 2 disappeared. Once the reactionwas complete the productethyl-3-{(5′-methylisoxazole-3′-carbonyl)-L-ValΨ(COCH₂)-L-(4-F-Phe)-L-((S)-Pyrrol-Ala)}-E-propanoatewas precipitated out of solution by the slow addition of water toreaction mixture. The resulting slurry was filtered to obtain a yieldof >85% white granular crystals of compoundethyl-3-{(5′-methylisoxazole-3′-carbonyl)-L-ValΨ(COCH₂)-L-(4-F-Phe)-L-((S)-Pyrrol-Ala)}-E-propanoatehaving a purity of >97%. The product may then be recrystallized bydissolving it in hot MeOH:EtOAc 1:1 followed by slow addition of hexanes(2 vols.)

[0147] It is to be understood that the foregoing description isexemplary and explanatory in nature, and is intended to illustrate theinvention and its preferred embodiments. Through routineexperimentation, the artisan will recognize apparent modifications andvariations that may be made without departing from the spirit of theinvention. Thus, the invention is intended to be defined not by theabove description, but by the following claims and their equivalents.

What is claimed is: 1 A process useful in synthesizing antipicornaviral compounds, comprising: (a) performing cyanomethylation of a compound of formula V using bis(trimethysily)amide and bromoacetonitrile to yield a compound of formula VI;

(b) performing reduction, then cyclization, and then deprotection of the compound of formula VI to yield a compound of formula VII; and

(c) performing oxidation and olefination of the compound of formula VII by reacting the compound of formula VII with a SO₃-pyridine complex to

 yield a reaction mixture and reacting the reaction mixture with a compound for formula VIII to form a compound of formula IV: wherein R₁ is H, F, an alkyl group, OH, SH, or an O-alkyl group; wherein each R₄₁ is independently H or lower alkyl; wherein is any suitable protecting group for nitrogen and wherein Z and Z₁ are each independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, —C(O)R₂₁, —CO₂R₂₁, CN, —C(O)NR₂₁R₂₂, —C(O)NR₂₁OR₂₂, —C(S)R₂₁, —C(S)NR₂₁R₂₂, —NO₂, —SOR₂₁, —SO₂R₂₁, —SO₂NR₂₁R₂₂, —SO(NR₂₁)(OR₂₂), —SONR₂₁, —SO₃R₂₁, —PO(OR₂₁)₂, —PO(R₂₁)(R₂₂), —PO(NR₂₁R₂₂)(OR₂₃), —PO(NR₂₁R₂₂)(NR₂₃R₂₄), —C(O)NR₂₁NR₂₂R₂₃, or —C(S)NR₂₁NR₂₂R₂₃, where R₂₁, R₂, R₂₃, and R₂₄ are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a thioacyl group, or where any of two of R₂₁, R₂₂, R₂₃, and R₂₄, together with the atom(s) to which they are bonded, form a heterocycloalkyl group, provided that Z and Z₁ are not both H; or Z₁ and R₁, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z₁ and R₁ are as defined above except for moieties that cannot form the cycloalkyl or heterocycloalkyl group; or Z and Z₁, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Z₁ are as defined above except for moieties that cannot form the cycloalkyl or heterocycloalkyl group.
 2. The process of claim 1, wherein the compound of formula V is prepared from N-Boc L glutanic acid γ-benzyl ester.
 3. The process of claim 1, wherein X is a Boc group.
 4. The process of claim 1, wherein R₄₁ is H.
 5. The process of claim 1, wherein Z is H.
 6. The process of claim 1, wherein Z₁ is —COOEt.
 7. A process useful in synthesizing antipicornaviral compounds according to claim 1, further comprising the steps of: (d) deprotecting the compound of formula IV to yield a compound of formula IVA:

 ; and (e) subjecting a compound of formula II and the compound of formula IVA to an amide-forming reaction to yield a compound of formula IA:

wherein each R₄₁ is independently H or lower alkyl; R₄ is

R₅ and R₆ are each independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; and Z and Z₁ are each independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, —C(O)R₂₁, —CO₂R₂₁, CN, —C(O)NR₂₁R₂₂, —C(O)NR₂₁OR₂₂, —C(S)R₂₁, —C(S)NR₂₁R₂₂, —NO₂, —SOR₂₁, —SO₂R₂₁, —SO₂NR₂₁R₂₂, —SO(NR₂₁)(OR₂₂), —SONR₂₁, —SO₃R₂₁, —PO(OR₂₁)₂, —PO(R₂₁)(R₂₂), —PO(NR₂₁R₂₂)(OR₂₃), —PO(NR₂₁R₂₂)(NR₂₃R₂₄), —C(O)NR₂₁NR₂₂R₂₃, or —C(S)NR₂₁NR₂₂R₂₃, where R₂₁, R₂₂, R₂₃, and R₂₄ are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a thioacyl group, or where any of two of R₂₁, R₂₂, R₂₃, and R₂₄, together with the atom(s) to which they are bonded, form a heterocycloalkyl group, provided that Z and Z₁ are not both H; or Z₁ and R₁, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z₁ and R₁ are as defined above except for moieties that cannot form the cycloalkyl or heterocycloalkyl group; or Z and Z₁, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Z₁ are as defined above except for moieties that cannot form the cycloalkyl or heterocycloalkyl group.
 8. The process of claim 7, wherein X is a Boc group.
 9. The process of claim 7, wherein compound IV is


10. The process of claim 7, wherein the compound of formula II is


11. The process of claim 7, wherein the compound of formula IVA is


12. The process according to claim 7, wherein the compound of formula IA is


13. A process useful in synthesizing antipicornaviral compounds, comprising: (a) performing dianionic alkylation of a compound of formula IX using bromoacetonitrile to prepare a compound of formula X;

(b) performing hydrogenation of the compound of formula X to yield an amine of formula XI;

(c) reacting the compound of formula XI with Et₃N to yield a lactam ester of formula XII;

(d) performing reduction of the lactam ester of formula XII to yield a compound of formula XIII:

(e) performing oxidation and olefination of the compound of formula XIII to yield a compound of formula XIV by reacting it with a compound of formula

wherein each R₄₁ is independently H or lower alkyl; Z and Z₁ are each independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, —C(O)R₂₁, —CO₂R₂₁, CN, —C(O)NR₂₁R₂₂, —C(O)NR₂₁OR₂₂, —C(S)R₂₁, —C(S)NR₁R₂₂, —NO₂, —SOR₂₁, —SO₂R₂₁, —SO₂NR₂₁R₂₂, —SO(NR₂₁)(OR₂₂), —SONR₂₁, —SO₃R₂₁, —PO(OR₂₁)₂, —PO(R₂₁)(R₂₂), —PO(NR₂₁R₂₂)(OR₂₃), —PO(NR₂₁R₂₃(NR₂₃R₂₄), —C(O)NR₂₁NR₂₂R₂₃, or —C(S)NR₂₁NR₂₂R₂₃, where R₂₁, R₂₂, R₂₃, and R₂₄ are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a thioacyl group, or where any of two of R₂₁, R₂₂, R₂₃, and R₂₄, together with the atom(s) to which they are bonded, form a heterocycloalkyl group, provided that Z and Z₁ are not both H; or Z and Z₁, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Z₁ are as defined above except for moieties that cannot form the cycloalkyl or heterocycloalkyl group; and X is any suitable protecting group for nitrogen.
 14. The process useful in synthesizing antipicornaviral compounds according to claim 13, further comprising: preparing a compound of formula IV by converting the compound of formula XIV to yield the compound of formula Iv:

wherein R₁ is H, F, an alkyl group, OH, SH, or a O-alkyl group.
 15. The process useful in synthesizing antipicornaviral compounds according to claim 14, further comprising: Step A: deprotecting the compound of formula IV to yield a compound of formula IVA:

Step B: subjecting a compound of formula II and the compound of formula IVA to an amide-forming reaction to yield a compound of formula IA:

wherein each R₄ is independently H or lower alkyl, R₄ is

R₅ and R₆ are each independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; and Z and Z₁ are each independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, —C(O)R₂₁, —CO₂R₂₁, CN, —C(O)NR₂₁R₂₂, —C(O)NR₂₁OR₂₂, —C(S)R₂₁, —C(S)NR₂₁R₂₂, —NO₂, —SOR₂₁, —SO₂R₂₁, —SO₂NR₂₁R₂₂, —SO(NR₂₁)(OR₂₂), —SONR₂₁, —SO₃R₂₁, —PO(OR₂₁)₂, —PO(R₂₁)(R₂₂), —PO(NR₂₁R₂₂)(OR₂₃), —PO(NR₂₁R₂₂)(R₂₃R₂₄), —C(O)NR₂₁NR₂₂R₂₃, or —C(S)NR₂₁NR₂₂R₂₃, where R₂₁, R₂₂, R₂₃, and R₂₄ are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a thioacyl group, or where any of two of R₂₁, R₂₂, R₂₃, and R₂₄, together with the atom(s) to which they are bonded, form a heterocycloalkyl group, provided that Z and Z₁ are not both H; or Z₁ and R₁, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloallyl group, where Z₁ and R₁ are as defined above except for moieties that cannot form the cycloalkyl or heterocycloalkyl group; or Z and Z₁, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Z₁ are as defined above except for moieties that cannot form the cycloalkyl or heterocycloalkyl group.
 16. The process of claim 13, wherein X is a Boc group.
 17. The process of claim 13, wherein R₄₁ is H.
 18. The process of claim 13, wherein Z is H.
 19. The process of claim 13, wherein Z₁ is —COOEt.
 20. The process of claim 14, wherein R₁ is H.
 21. A process useful for the synthesis of a compound of formula IA′, and acid addition salts thereof:

comprising the steps of: preparing a compound of formula IV′:

comprising: performing cyanomethylation of a compound of formula V′ using bis(trimethysily)amide and bromoacetonitrile to yield a compound of formula VI′;

performing reduction, then cyclization, and then deprotection of the compound of formula VI′ to yield a compound of formula VII′; and

performing oxidation and olefination of the compound of formula VII by reacting the compound with a SO₃-pyridine complex before the resulting reaction mixture is reacted with Ph₃P═CHCO₂Et; deprotecting the compound of formula IV to yield a compound of formula IVA′:

subjecting a compound of formula II′ and the compound of formula formula IVA′ to an amide-forming reaction;


22. The process of claim 21, wherein the compound of formula V is prepared from N-Boc L glutanic acid γ-benzyl ester.
 23. A process useful in synthesizing antipicornaviral compounds, comprising: (a) performing dianionic alkylation of a compound of formula IX′ using bromoacetonitrile to prepare a compound of formula X′;

(b) performing hydrogenation of the compound of formula X′ to yield an amine of formula XI′;

(c) reacting the compound of formula XI′ with Et₃N to yield a lactam ester of formula XII′; (d) performing reduction of the lactam ester of formula XII′ to yield a compound of formula XIII′:

(e) performing oxidation and olefination of the compound of formula XIII′ to yield a compound of formula XIV′ by reacting it with Ph₃P═CHCO₂Et;


24. The process useful in synthesizing antipicornaviral compounds according to claim 23, further comprising: converting the compound of formula XIV′ to the compound of formula IV′;


25. The process useful in synthesizing antipicornaviral compounds according to claim 24, further comprising: deprotecting the compound of formula IV′ to yield a compound of formula IVA′:

 ; and subjecting a compound of formula II′ and the compound of formula IVA′ to an amide-forming reaction;


26. A compound having formula III, made by the process of claim
 25. 27. A process for forming intermediate IV′, useful for synthesizing antipicornaviral compounds comprising

performing dianionic alkylation of a compound of formula IX′ using

bromoacetonitrile to prepare a compound of formula X′


28. The process of claim 27 further comprising hydrogenating the compound of formula X′ to yield an amine of formula XI′


29. The process of claim 27 further comprising hydrogenating the compound of

formula X′ with hydrogen and PtO₃ to yield an amine of formula XI′A′
 30. The process of claim 28 further comprising reacting the compound of formula XI′ with Et₃N to yield a lactam ester of formula XII′


31. The process of claim 29 further comprising reacting the compound of formula XI′A with Na₂CO₃ to yield a lactam ester of formula XII″


32. The process of claim 30 further comprising performing a reduction of the lactam ester of formula XII′ to yield a lactam alcohol of formula XIII′


33. The process of claim 31 further comprising performing a reduction of the

lactam ester of formula XII′ to yield a lactam alcohol of formula XIII
 34. The process of claim 33 further comprising oxidizing the lactam alcohol of formula XIII′, then olefination by treating the oxidized lactam alcohol with Et₃P, and BrCH₂CO₂Et in the presence of base to yield a compound of formula IV′


35. A process for forming intermediate IV′, useful for synthesizing antipicornaviral compounds comprising

oxidizing the lactam alcohol of formula XIII′, then olefination by treating the oxidized lactam alcohol with a Wittig reagent to yield a compound of formula IV′.
 36. The process of claim 35 further comprising reducing the lactam ester of formula XII′ to yield a lactam alcohol of formula XIII′


37. The process of claim 36 further comprising reacting the salt of the compound of formula XI′B with base to yield a lactam ester of formula XII′


38. The process of claim 37 further comprising hydrogenating the compound of formula X′ ti yield a compound of formula XI′B


39. The process of claim 38 further comprising performing dianionic alkylation of a compound of formula IX′ to prepare a compound of formula X′ 